6.7
M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or hal…
A cell’s transition into mitosis is characterized by the activation of M-Cdk complexes, consisting of the protein kinase Cdk1—or cyclin-dependent kinase 1—bound to M cyclin.
M-Cdk complexes form when M cyclin accumulates. In most cells, M cyclin levels peak during G2—the gap phase following the chromosomal duplication of S phase—and early mitosis.
The M-Cdk complex is phosphorylated at an active site by CDK-activating kinase, or CAK. However, the complex remains inactive, because it is also phosphorylated at two inhibitory sites by the protein kinase Wee1.
M-Cdk is activated largely by the protein phosphatase Cdc25. Cdc25 removes the phosphates that inhibit M-Cdk and suppresses the inhibitory activity of Wee1.
M-Cdk drives the transition into mitosis by activating factors necessary for early mitotic processes.
In prophase, M-Cdk activity spurs the shortening and compaction of chromosomes, known as chromosome condensation. During prophase, M-Cdk also initiates the formation of the mitotic spindle—which separates chromosomes into two daughter cells.
During prometaphase in animal cells, M-Cdk helps degrade the nuclear envelope, allowing the nucleus to break apart.
In metaphase, M-Cdk mediates the attachment of sister chromatids to opposite poles of the spindle.
M-Cdk promotes the multiphase reorganization of the Golgi apparatus, which is important for correct spindle formation and segregation of the organelle. In addition, throughout mitosis, M-Cdk is involved in the reorganization of the actin cytoskeleton, which helps determine spindle orientation and the axis of cell division, among other functions.
View the full transcript and gain access to JoVE Core videos
Q1: What is M-Cdk and how does it form?
M-Cdk is a protein complex consisting of Cdk1 (cyclin-dependent kinase 1) bound to M cyclin. It forms when M cyclin accumulates during G2 phase and early mitosis. M cyclin levels peak at this time, allowing it to bind to the stable Cdk1 protein, creating the active M-Cdk complex that drives the transition into mitosis.
Q2: How is M-Cdk activated in the cell?
M-Cdk activation is a multi-step process. First, CAK (CDK-activating kinase) phosphorylates the complex at an active site. However, Wee1 kinase phosphorylates two inhibitory sites, keeping M-Cdk inactive. The phosphatase Cdc25 then removes these inhibitory phosphates and suppresses Wee1 activity, fully activating M-Cdk for mitotic progression.
Q3: What mitotic processes does M-Cdk control during prophase?
During prophase, M-Cdk drives chromosome condensation, the shortening and compaction of chromosomes necessary for proper segregation during cell division. M-Cdk also initiates formation of the mitotic spindle, which is essential for separating chromosomes into two daughter cells. These early mitotic processes are critical for successful cell division.
Q4: How does M-Cdk affect the nuclear envelope and sister chromatids?
During prometaphase, M-Cdk helps degrade the nuclear envelope, allowing the nucleus to break apart and chromosomes to access spindle machinery. In metaphase, M-Cdk mediates the attachment of sister chromatids to opposite poles of the mitotic spindle, ensuring proper chromosome segregation and accurate distribution to daughter cells.
Q5: What role does M-Cdk play in organizing cellular structures during mitosis?
M-Cdk promotes multiphase reorganization of the Golgi apparatus, which is critical for correct spindle formation and proper organelle segregation between daughter cells. Throughout mitosis, M-Cdk also reorganizes the actin cytoskeleton, which determines spindle orientation and the axis of cell division, ensuring coordinated cellular reorganization.
Q6: Are other kinases involved in the G2/M transition besides M-Cdk?
Yes, polo-like kinases and Aurora kinases also regulate the G2/M transition. Plk1 is necessary for bipolar mitotic spindle formation and phosphorylates proteins that separate spindle poles. Aurora-A regulates spindle formation and stabilization, while Aurora-B enables sister chromatid attachment to the spindle, working alongside M-Cdk.
Q7: Why do M cyclin levels fluctuate while Cdk levels remain stable?
M cyclin gene transcription increases as cells approach the G2/M transition, causing M cyclin accumulation and binding to stable Cdk1 protein. After mitosis, M cyclin is degraded, while Cdk1 levels persist throughout the cell cycle, allowing different cyclins to bind and regulate distinct phases. This ensures precise cell cycle control.